Overall objectives are to study membrane NaK-ATPase activity and endogenous ouabain-like regulatory factors in bipolar affective disorder, and to study the effects of lithium therapy on phosphoinositide metabolism. A major aim is to determine whether there is a variant of the NaK-ATPase which is specific for bipolar affective disorder. Radioactive photoaffinity labels will be developed which will label both the alpha and beta subunits of the enzyme in erythrocyte membranes and in post mortem brain tissue. Methods will be developed for the separation of the labeled enzyme subunits and selective degradation products. These will be used to determine whether a variant form of the enzyme can be demonstrated in bipolar affective disorder. If successful, an attempt will be made to develop a diagnostic test for the disorder, based on these findings. A second aim is to investigate whether there may be abnormal regulation of NaK-ATPase activity by an endogenous ouabain-like factor in bipolar affective disorder. Factors which inhibit NaK-ATPase activity and displace ouabain-binding will be isolated from animal brain and other tissues. These will be tested against erythrocyte NaK-ATPase from bipolar and normal subjects to determine whether there is any difference in affinity or extend of inhibitory activity. Possible changes in affinity or susceptibility to inhibition by these factors during lithium therapy will be followed. Methodology will be developed for the assay of circulating ouabain-like inhibitory factor in extracts of blood plasma. Circulating levels of inhibitory factor will be measured in normal and bipolar subjects, and during lithium therapy. A third aim is to determine whether the responsivity of the membrane phosphoinositide signal system changes during lithium therapy. Responses which involve the phophoinositide signal system will be measured in platelets from patients receiving lithium therapy and compared with responses before lithium therapy and in normal controls. The levels of inosito, inositol phosphates, phosphoinositides and other lipids will be measured in lymphocytes, platelets and erythrocytes from patients receiving lithium therapy and will be compared with the levels in normal controls.